KR20040099158A - Solid Formulation for Medicine Comprising Sparingly Soluble Drug and Process for Preparing the Same - Google Patents

Abstract

PURPOSE: A method of making a solid preparation by previously dissolving poorly soluble drugs in a plasticizer and then coating a powdery enteric coating agent on a core particle while spraying the plasticizer on the core particle is provided. It can produce the product having excellent solubility without organic solvents utilizing conventional equipment while avoiding the problems such as environmental pollution, work site safety or the like. CONSTITUTION: The pharmaceutical solid preparation contains: a core particle; a plasticizer in which poorly soluble drugs for coating the core particle are dissolved; and a powdery enteric coating agent. The plasticizer is triethyl citrate or polyethylene glycol. The enteric coating agent contains one or more selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, hydroxypropylmethylcellulose acetate maleate. The enteric solid preparation is prepared by coating a powdery enteric coating agent on a core particle while spraying a plasticizer in which poorly soluble drugs are dissolved on the core particle.

Description

Solid Formulation for Medicine Comprising Sparingly Soluble Drug and Process for Preparing the Same}

The present invention relates to a method for producing a solid preparation for the purpose of improving the dissolution of poorly soluble drugs. More specifically, the present invention relates to a formulation coated with a solvent-free enteric coating using a plasticizer in which a poorly soluble drug is dissolved.

In recent years, drugs newly developed have many poorly soluble properties, and improvement of their solubility and absorption is an important problem. In order to increase the solubility and absorption of the drug, various formulation methods have been proposed such as drug miniaturization, amorphous, solid dispersion, etc. Among these, solid dispersion has been widely studied as a method for dispersing the drug in an inert carrier.

Some methods have been proposed as a method for producing a solid dispersion, but in particular, a solvent method may be mentioned.

The solvent method is a method for producing a solid dispersion by dissolving a drug and a water-soluble polymer as a carrier in a solvent such as an organic solvent and then distilling off the solvent, or dissolving the drug in a solvent and dispersing it in a carrier. . By dissolving the poorly soluble drug in a solvent, it is thought that the drug is amorphous and can be dispersed in the carrier in this state, thereby improving the solubility and the absorbency.

As a specific example of the solvent method, Nippidipine and poly of a poorly water-soluble drug are granulated in Japanese Patent Application Laid-Open No. 3-1288 and Japanese Patent No. 3028404 in the form of granules made of a water-soluble polymer such as hydroxypropyl cellulose. It has been reported to obtain a solid dispersion by spraying and drying a liquid obtained by dissolving a polymer base such as vinylpyrrolidone, hydroxymethyl cellulose or methyl cellulose in an organic solvent.

In addition, Japanese Patent Application Laid-Open No. 2000-281561 discloses a poorly water-soluble drug such as cycloheptadines and water-soluble polymers such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose and hydroxypropyl cellulose in water / alcohol system. Solid dispersions are prepared by spray granulation with lactose.

Japanese Patent Application Laid-Open No. 11-116502 discloses a composition comprising a poorly soluble drug and hydroxypropyl cellulose acetate succinate dissolved in an organic solvent and spray-dried directly in the air stream of a fluidized bed without being sprayed on a carrier such as lactose. The solid dispersion is obtained by the method.

Of the conventional methods for producing a solid dispersion, the solid dispersion obtained by the solvent method is excellent in terms of improving the solubility and absorption of poorly soluble drugs, but in this solvent method, volatile organic solvents such as dichloromethane, acetone, and alcohols are used. In many cases, industrial problems such as residual organic solvents in the product, environmental pollution, workplace safety, or equipment investment required to avoid these problems have occurred.

As a result of earnestly researching for the purpose of solving the said subject, the inventors of the present invention discovered the method of manufacturing a solid dispersion, without using the organic solvent used by the conventional solvent method. That is, after dissolving the poorly soluble drug in a plasticizer in advance, it is found that a solid formulation having excellent solubility is obtained by performing a solvent-free coating coated on the nucleus particles with the fine powdery enteric coating agent, thereby completing the present invention. Reached. According to the present invention, it is possible to manufacture a solid preparation using an existing equipment or technology without using an organic solvent as in the prior art, and the obtained solid preparation can obtain the same superior elution improvement effect as the conventional solvent method. I could confirm it.

The present invention specifically provides a method for producing an enteric solid preparation which coats a powdery enteric coating agent while dispersing a plasticizer in which a poorly soluble drug is dissolved in nuclear particles. The present invention also provides an enteric solid preparation comprising a nucleus particle, a plasticizer in which the poorly soluble drug covering the nucleus particle is dissolved, and a powdery enteric coating agent.

<Embodiment of the invention>

The poorly water-soluble drug used in the present invention has a very low solubility in water, and is generally a poorly absorbable drug in oral administration. For example, drugs that are classified as "almost unresolved" or "very difficult to dissolve" as defined by the Japanese pharmacy. The solubility of drugs in Japanese pharmacies refers to the degree of melting within 30 minutes when the drug is solid, made into powder and then poured into a solvent and shaken vigorously for 30 seconds at 20 ± 5 ° C for 5 minutes. Almost insoluble "means more than 10,000 ml of solvent (in this case, water) required to dissolve 1 g or 1 ml of drug, and" very difficult to dissolve "means more than 1,000 ml and 10,000 ml of solvent required to dissolve 1 g or 1 ml of drug. I say less than constellation. Examples of specific poorly soluble drugs include ibuprofen, indomethacin, nifedipine, phenacetin, phenytoin, digitoxin, digoxin, nirupadipine, diazepam, griseofulvin, chloramphenicol, sulfatiazole and the like.

The plasticizer used in the present invention is not particularly limited as long as it has a property of dissolving the poorly soluble drug by heating to room temperature or 90 ° C. or lower and fusing the fine powdery enteric coating agent in a hydrophobic manner. For example, propylene glycol, triethyl citrate, polyethylene glycol, acetyl monoglycerides, glycerin, tributyl citrate, triacetin, diacetin, monoacetin, diethyl phthalate, and the like can be given. Especially, triethyl citrate and polyethylene glycol are preferable. The plasticizer can be used as one kind or a mixture of two or more kinds. Since these plasticizers are used for the purpose of improving the plasticity of the coating film and forming a more uniform film, the amount of the plasticizer is not particularly limited as long as it is necessary to achieve the purpose, but preferably 1 to 20 parts by weight based on 1 part by weight of the soluble drug. Part, more preferably in the range of 5 to 15 parts by weight, it is preferable to add a minimum part by weight of the drug is sufficiently dissolved in the plasticizer.

It is also useful to improve the solubility of drugs and plasticizers by adding hydrophobic waxes such as surfactants, fats and oils, higher alcohols, higher fatty acids and glycerin fatty acid esters.

In the present invention, in order to spread and coat the fine powdery enteric coating base, preferred nuclear particles (carriers) that can be applied include lactose, sucrose, glucose, trehalose, fructose, dextrin, starch, pullulan, and carboxymethyl. Cellulose and salts thereof, carboxymethyl starch and salts thereof, cellulose, crystalline cellulose, polyvinyl alcohol, hemicellulose and the like, as well as white sugar, starch spherical granules, purified white sugar spherical granules, lactose and crystalline cellulose spherical granules. And other granules and fine granules of solid preparations.

The average particle diameter of the nuclear particles is preferably 75 to 1700 µm, particularly 100 to 1400 µm. The nucleus particles are preferably selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, shellac and the like and undercoated. The amount of undercoat is preferably 1 to 10% by weight based on the weight of the nucleus particles in view of the protection of the nucleus particles in the coating and the uniformity of the coating film.

The enteric coating agent used in the present invention may preferably be a fine powder having an average particle diameter of 10 μm or less, more preferably 1 to 10 μm, and, for example, cellulose acetate phthalate (CAP), cellulose acetate trimellitate ( CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose trimellitate (HPMCT), hydroxypropylmethylcellulose acetate maleate (HPMCAM), carboxy Methyl ethyl cellulose (CMEC) is used, and a copolymer of methacrylic acid and ethyl acrylate is used as the acrylic system. The enteric coating agent used in the present invention preferably contains a cellulose derivative, particularly preferably hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose trimellitate (HPMCT) and hydroxypropylmethyl. At least one selected from the group consisting of cellulose acetate maleate (HPMCAM). When the average particle diameter exceeds 10 µm, the coating agent does not adhere well to the granules, and a solid formulation in which the drug is uniformly dispersed may not be obtained.

Among these coatings, hydroxypropylmethylcellulose acetate succinate (HPMCAS) having a low softening temperature and excellent film formability is suitable.

Moreover, it can also be made into a sustained-release preparation by using together fine powder of polymers other than an enteric coating agent, for example, ethyl cellulose and an acrylic polymer.

In order to carry out the present invention, since no solvent is used, a large drying capacity is not required, and some heating and stirring is performed for the leading edge and fusion of the dispersed fine powdery enteric coating agent and for good dispersion of the drug. It is preferable to have a capability, and a full-flow fluid coating apparatus, a pan coating apparatus, a fluidized bed coating apparatus, etc. are mentioned, for example. Of these coating apparatuses, centrifugal flow coating apparatuses with appropriate agitation capabilities are suitable.

In the method for producing a solid preparation according to the present invention, for example, while the core particles of lactose are stirred and electrically rolled in the above-described centrifugal electrocoating apparatus, the poorly soluble drug is dissolved in a liquid or a heat-melted liquid plasticizer at room temperature, and then dispersed therein. For example, spraying), and at the same time, enteric coating agents having an average particle diameter of 10 µm or less are dispersed to coat the nuclear particles. Such a series of operations can also be carried out by dividing the composition several times and changing the composition. Further, for the purpose of preventing the adhesion between the granules during coating, it may be used in combination with the dispersion, such as talc, a car flex (SiO _2), magnesium stearate, corn starch.

The weight ratio of the plasticizer and the enteric coating agent in the present invention, and the coating amount on the nucleus particles are important factors in improving solubility.

The weight ratio of the plasticizer and the enteric coating agent is preferably in the range of approximately plasticizer: enteric coating agent = 2: 8 to 8: 2.

Preferred coating amounts range from about 10 to 50% by weight of the coated enteric coating, relative to the weight of the nucleus particles.

The solid preparation obtained as mentioned above can also be coat | covered with another high molecular compound after that. In addition, it is also possible to add pharmaceuticals, additives (plasticizers, colorants, pigments, anti-sticking agents (talc), fats and oils, etc.) which are conventionally formulated into these coatings.

In addition, water-soluble polymers such as talc, carplex, magnesium stearate and calcium stearate, water-soluble polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, carnauba wax, etc. It is also possible to coat | cover further the solid preparation obtained with 1 type, or 2 or more types of mixtures chosen from waxes, such as a white beeswax and a paraffin.

<Example>

Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited to these Examples.

<Example 1>

Prior to preparation of the solid preparation of the present invention, 500 g of nuclear granules (Nonparel 101, Float Sangyo Co., Ltd., 20 to 24 ^# ) are placed in an electric flow coating device (CF Coater CF-360 manufactured by Float Sangyo Co., Ltd.), and A 5 wt% aqueous solution of oxypropyl methyl cellulose (manufactured by TC-5R Shin-Etsu Chemical Co., Ltd.) was sprayed to undercoat the amount of hydroxypropyl methyl cellulose to the nucleus granules to 5 wt%.

500 g of the nuclear granules thus prepared were placed in a centrifugal electric coating device (CF coater CF360, manufactured by Floint Sangyo Co., Ltd.), and 25 g of nifedipine as a poorly soluble drug at an intake temperature of 60 ° C, a product temperature of 40 ° C, and a rotation speed of 200 rpm. Hydroxypropylmethylcellulose acetate succinate (average particle size 5 µm, Shin-Etsu Chemical Co., Ltd.) while spraying at a rate of 13.75 g / min using a mixed liquid of 75 g of triethyl citrate and 175 g of polyethylene glycol 400 having dissolved Product AS-MF, each substituent content is 11.0% by weight of succinoyl group, 9.3% by weight of acetyl group, 7.4% by weight of hydroxypropoxyl group, 23.0% by weight of methoxyl group) 250 g and 150 g of talc. The coating was done by adding at a rate of 20 g / min. Thereafter, 20 g of a capflex (hard silicic anhydride) was dispersed as an anti-adherent agent of granules, and stirred for 10 minutes at a product temperature of 40 ° C as post-drying. The yield was 95%. Treatment time was 30 minutes.

The obtained solid preparation was subjected to the dissolution test in the second liquid in accordance with the Japanese Drugstore 12 Dissolution Test Method. At the time of a test, when the sample of 50 microgram / mL equivalency was injected into nifedipine, the nifedipine dissolution rate after 45 minutes was 45 microgram / mL. This was above the 10 μg / mL solubility of nifedipine alone, indicating that the drug was in a supersaturated state in solution. Therefore, the dissolution of the drug was improved in the solid preparation prepared in the present invention.

<Example 2>

Hydroxypropylmethylcellulose acetate succinate of Example 1 was hydroxypropylmethylcellulose acetate succinate (average particle diameter 5 탆, Shin-Etsu Chemical Co., Ltd. AS-LF, each substituent content is 14.8% by weight succinoyl group, acetyl group 7.3 weight%, hydroxypropoxyl group 7.1 weight%, and methoxyl group 22.7 weight%), The solid preparation was manufactured by the same method.

About the obtained solid preparation, the elution test with the 2nd liquid was performed similarly to Example 1, and the dissolution rate of nifedipine after 60 minutes was 40 microgram / mL. This was above the 10 μg / mL solubility of nifedipine alone, indicating that the drug was in a supersaturated state in solution. Therefore, the dissolution of the drug was improved in the solid preparation prepared in the present invention.

<Example 3>

The hydroxypropyl methyl cellulose acetate succinate of Example 1 was hydroxypropyl methyl cellulose acetate succinate (average particle diameter 5 micrometers, Shin-Etsu Chemical Co., Ltd. AS-HF, content of each substituent is 7.8 weight% of a succinoyl group, an acetyl group A solid preparation was prepared in the same manner except for changing to 11.1 wt%, 7.4 wt% of hydroxypropoxyl group, and 23.5 wt% of methoxyl group.

About the obtained solid preparation, the elution test to the 2nd liquid was performed like Example 1, and the dissolution rate of nifedipine after 60 minutes was 45 microgram / mL. This was above the 10 μg / mL solubility of nifedipine alone, indicating that the drug was in a supersaturated state in solution. Therefore, the dissolution of the drug was improved in the solid preparation prepared in the present invention.

<Example 4>

500 g of the nuclear granules prepared in Experiment 1 were placed in a centrifugal motor coating apparatus (CF coater CF360), and triethyl citrate dissolved 25 g of nifedipine, a poorly soluble drug, at an intake temperature of 60 ° C, a product temperature of 40 ° C, and a rotation speed of 200 rpm. Hydrolysis of hydroxypropylmethylcellulose acetate while spraying at a rate of 28.25 g / min using a plasticizer of 17.5 g, 10 g of mybaset (glycerin fatty acid ester) and 230 g of polyethylene glycol 6000 were heated and dissolved at 60 ° C as a plasticizer. Powder was uniformly mixed with 50 g of Nate (average particle size 5 µm, Shin-Etsu Chemical Co., Ltd. AS-MF) and 30 g of talc at a rate of 8 g / min to perform coating. Thereafter, 20 g of a caplex (hard silicic anhydride) was dispersed as an anti-adherent agent of granules and stirred at a product temperature of 40 ° C. for 10 minutes. The yield was 87%. Treatment time was 20 minutes.

The obtained solid preparation was subjected to the dissolution test in the second liquid in accordance with the Japanese Drugstore 12 Dissolution Test Method. At the time of a test, when 50 microgram / mL equivalence sample was injected into nifedipine, the nifedipine dissolution rate after 60 minutes was 40 microgram / mL. This was above the 10 μg / mL solubility of nifedipine alone, indicating that the drug was in a supersaturated state in solution. Therefore, the dissolution of the drug was improved in the solid preparation prepared in the present invention.

Example 5

A solid preparation was prepared in the same manner except that the hydroxypropylmethylcellulose acetate succinate of Example 1 was changed to hydroxypropylmethylcellulose trimellitate (average particle diameter 5 µm, manufactured by Shin-Etsu Chemical Co., Ltd.).

The dissolution test of the obtained solid preparation in the second liquid in the same manner as in Example 1 showed that the dissolution rate of nifedipine after 60 minutes was 30 µg / mL, and the drug was in a supersaturated state in the solution. Therefore, the dissolution of the drug was improved in the solid preparation prepared in the present invention.

Comparative Example 1

500 g of the nuclear granules prepared in Experiment 1 were placed in a centrifugal electric coating device (CF Coater 360, Float Sangyo Co., Ltd.), and 25 g of nifedipine, a poorly soluble drug, at an intake temperature of 40 ° C, a product temperature of 36 ° C, and a rotation speed of 200 rpm. And 50 g of hydroxypropylmethylcellulose acetate succinate (AS-MF) powder in 700 g of a mixed solvent of methylene chloride / ethanol (1: 1 weight ratio), followed by spraying at a rate of 20 g / min, Solid formulations were prepared by a solvent method using an organic solvent.

About the obtained solid preparation, the elution test to the 2nd liquid was performed like Example 1, and the dissolution rate of nifedipine after 60 minutes was 45 microgram / mL.

Comparative Example 2

A solid preparation was prepared in the same manner as in Comparative Example 1 except that the hydroxypropylmethylcellulose acetate succinate of Comparative Example 1 was changed to hydroxypropylmethylcellulose trimellitate.

The dissolution rate of nifedipine after 60 minutes was 30 microgram / mL when the elution test to the 2nd liquid was performed like the Example about the obtained solid preparation.

From the above results, it was found that the solid preparation produced by the production method of the present invention improved the dissolution of poorly soluble drugs in the same manner as the solid preparation obtained by the conventional method.

According to the present invention, it is possible to prepare enteric solid preparations which have improved the dissolution of poorly soluble drugs simply by using existing equipment without using an organic solvent. In addition, the solid preparation in this invention had the same elution property as the solid preparation obtained by the conventional solvent method.

Claims (6)

An enteric solid preparation comprising a nucleus particle, a plasticizer in which a poorly soluble drug covering the nucleus particle is dissolved, and a powdery enteric coating agent. The enteric solid preparation according to claim 1, wherein the plasticizer is triethyl citrate or polyethylene glycol. The enteric solid preparation according to claim 1 or 2, wherein the enteric coating agent has an average particle diameter of 10 µm or less. The enteric solid preparation according to claim 1 or 2, wherein the enteric coating agent comprises a cellulose derivative. The method of claim 1 or 2, wherein the enteric coating agent is at least one selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, hydroxypropylmethylcellulose acetate maleate. Enteric solid preparations comprising. A method for producing an enteric solid preparation, wherein the core particle is coated with a powdery enteric coating agent while spreading a plasticizer in which a poorly soluble drug is dissolved.